In order to evaluate early proteins as therapeutic vaccine targets in AIDS, we will perform immunization studies in macaques previously infected with SIV. This SIV model most appropriately reflects the pathogenesis of HIV in humans. These studies are designed to extend our work developing a vaccine approach targeting HIV-1 Tat protein. We will initially compare the potency and potential efficacy of an SIV Tat Toxoid vaccine in animals initiating HAART therapy during the chronic phase of SIV infection. Immune responses to early and late viral antigens, including the immunogen, will be monitored prior to HAART, during HAART and after discontinuation of HAART. We will test the hypothesis that the Tat vaccine, alone or in combination with low dose IL-2, can promote anti-viral immune responses in chronically infected animals. Sequence analysis and peptide mapping studies will be used to determine if selective pressure is induced by vaccine administration, to characterize the immune response, and to identify escape variants. A second animal study will be performed during the 3rd and 4th year which will deliver a combination of the early proteins. Tat, Rev, and Nef, where Rev and Nef are fused to the basic domain of Tat for uptake. Our strategy will take advantage of the ability of this region of Tat to enter the MHC class-I processing pathway and elicit CD8+ T cell responses to the fused protein component. This strategy will further test the hypothesis that multiple early gene targets may better control virus replication and minimize escape, particularly in view of the function of Nef in downregulating MHC class-I expression. The comparison of a late gene fused to Tat (i.e. Tag-Gag) will permit the determination of the added contribution of a late gene target where immune responses have been previously well characterized in this model. These studies are designed to evaluate the concept of a therapeutic Tat vaccine component in an animal model for lentiviral infection. Since our protein-based strategy stimulates both humoral and cellular (CD4+ and CD8+) immune responses, we propose to extend this protein-based strategy with additional targets. By analogy with antiviral pharmacotherapy, a multi-target vaccine should provide the best long-term protection from viral escape. The goal of this project is to generate the necessary information in an animal model to determine the feasibility of this approach. This information should provide the conceptual framework for a protein vaccine strategy in humans based on Tat and including additional early viral immunogens. If successful, this strategy may be beneficial in further controlling HIV infection and may permit patients treated with HAART during chronic infection to realize independence from pharmacotherapeutic regimens.